Effect of Adjunctive Simvastatin on Depressive Symptoms Among Adults With Treatment-Resistant Depression

Key Points Question Does adjunctive treatment with 20 mg/d of simvastatin lead to an improvement in depressive symptoms in adults with treatment-resistant depression? Findings In this randomized clinical trial of 150 participants with treatment-resistant unipolar depression, 12 weeks of 20 mg/d of simvastatin added to standard care did not show a statistically significant benefit compared with placebo added to standard care on the overall course of depressive symptoms. Meaning In this study, simvastatin was not beneficial for the treatment of symptoms of treatment-resistant depression compared with standard care.


Background 20
Major depressive disorder (MDD) is a leading source of disability worldwide [1]. At least a 21 third of people with MDD fail to respond to an adequate trial with first-line antidepressants Statins are pleiotropic agents and accumulating evidence from preclinical studies has 29 suggested that these agents may have antidepressant properties [4,5]. A recent population- 30 based study indicated that concomitant use of statins and selective serotonin reuptake 31 inhibitors (SSRIs) resulted in significantly less psychiatric hospital contacts due to depression 32 compared to people who used SSRIs alone [6]. Moreover, a meta-analysis of population-33 based studies has suggested that statin use may decrease the risk of incident depression [7]. In 34 addition, a recent meta-analysis of three small randomised controlled studies (RCTs) have 35 provided evidence that adjunctive treatments with statins could be efficacious for treatment of 36 depressive symptoms in patients with moderate-to-severe depression [8].  [5, [9][10][11] Aberrations in these pathways have been increasingly implicated in the 41 neurobiology of depression [12][13][14]. Moreover, abnormalities in lipid metabolism have also been implicated in the pathophysiology of depression, specifically for the development of 43 atypical depressive symptoms i.e. increased appetite and/or weight gain, hypersomnia, leaden 44 paralysis, fatigue and interpersonal sensitivity [15,16]. Hence lipid-lowering effects of statins 45 may also play a role in putative antidepressant effects of this class of drugs. Data from the 46 STAR*D trial indicate poorer treatment response to SSRIs in those with atypical depression 47 and therefore, statins could provide genuinely novel therapeutic targets for this group of 48 people with TRD [17].

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We plan to carry out an RCT involving 150 participants with treatment-resistant depression, 51 with the aim of determining whether the addition of simvastatin (20mg daily), a lipophilic 52 statin that readily crosses the blood-brain barrier [18,19], to treatment as usual (TAU) for 12 53 weeks leads to a reduction in depressive symptoms compared with placebo added to TAU. 54 We predict that treatment-resistant depression patients will show improvement in mood with 55 simvastatin treatment and that the response will be associated with reduction in lipid 56 biomarkers (i.e. plasma LDL and LDL/HDL ratio). A secondary hypothesis relates to 57 simvastatin's effects on putative inflammatory biomarkers. High LDL and low HDL 58 contribute substantially to immunological up-regulation in the development of 59 atherosclerosis. Pro-inflammatory cytokine (Interleukin-6 and Tumour Necrosis Factor) 60 levels are often altered in depressed patients and decreased by successful antidepressant 61 therapy [20,21]. We therefore predict that in those treatment-resistant depression patients 62 who show improvement in mood with simvastatin treatment, that response will be associated 63 with reduction in inflammatory biomarkers. Our mechanistic hypothesis is that the anti-64 inflammatory and lipid-reducing effects of simvastatin will improve neuroinflammation and 65 thus mediate a response to simvastatin.

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A pragmatic multi-centre, 12-week, double blind, placebo controlled randomised trial of 68 simvastatin added to treatment as usual (TAU) for patients suffering from a DSM-5 major 69 depressive episode that has failed to respond to at least two trials of antidepressants. This will 70 be a parallel group study with 75 participants in each arm. Recruitment will occur at 71 outpatient psychiatric clinics in Karachi, Lahore, Hyderabad, Rawalpindi and Quetta Participants will be randomised to receive either simvastatin and treatment as usual (TAU), or 83 placebo and TAU for 12 weeks. All participants will provide written informed consent after to patients with depressive disorders in Pakistan. Simvastatin added to TAU will be 20mg 88 taken once daily. This dose has been found to be safe and well tolerated as well as effective 89 in reducing depressive symptoms in a population with moderate to severe depression [22]. 91 The trial has been registered with Clinicaltrials.gov in (ClinicalTrials.gov identifier: 92 NCT03435744).

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Sample Size 95 We estimate a moderate effect size of 0.60 will be reported at week 12. Assuming a type-1 96 error of 5%, we will need to follow up 120 patients across the two groups to achieve 90% 97 power at Week 12. With an anticipated dropout rate of 20% by Week 12, we will randomise  Initially, the research team will approach local clinical teams to inform them about the trial 107 and provide them with the inclusion and exclusion criteria. They will then ask psychiatrists in 108 each outpatient department if they are able to identify any patients who may be potentially 109 eligible to take part in the study. The consultant psychiatrist will briefly explain the study to 110 the patient and if the patient agrees, consultants will refer patients to the research team.

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Researcher staff will work closely with the clinical team to determine if patients are suitable 113 to participate in the trial. If patients meet the inclusion criteria, and the consultant psychiatrist 114 and clinical team agree that they could be potential participants, the research assistant (RA) 115 will arrange an appointment to explain the study verbally and provide them with the 116 participant information sheet. The patient will be given at least 24 hours to read and 117 understand this leaflet. If after this they decide that they are willing to take part, an 118 appointment will be arranged to obtain signed informed consent for trial participation and 119 also signed consent for access to their medical notes. Literate participants will sign the 120 consent forms but, if the participant cannot read and sign the consent form, his/her caregiver 121 and/or an independent person who the participant agrees to be a witness, will be requested to 122 read the participant information leaflet and consent form to patient. Participants will then be 123 asked to place a thumbprint on the consent form if they agree to participate, which will be 124 countersigned by a witness/caregiver. Depression (HRSD-24) will be used to assess severity and a score ≥14 will be used as the 132 minimum threshold for study entry [25]. All patients must currently be on an antidepressant and must have had a non-response to >2 135 oral antidepressant treatments in the current episode (including the one they are currently taking). The >2 antidepressants must have been taken for at least 6 weeks at least at the 137 minimum therapeutic dose according to British National Formulary (BNF) [26] and 138 Maudsley prescribing guidelines [27]. Relapse whilst on an antidepressant will also count as 139 a failed treatment trial. During the twelve weeks of active/placebo treatment patients will be 140 requested to remain on a stable dose of the antidepressant they are taking. Participants will 141 not be permitted to start a psychosocial intervention or psychotherapy during the study 142 period, however those who were already engaged in these treatments at the screening stage 143 will be permitted to continue their treatment.  Randomisation service will be provided by an independent statistical support service based in 175 the UK. We will stratify randomization based on severity of depressive symptoms at baseline 176 and study centre. Participants will be assigned to groups via random generation of allocation 177 sequence, balanced across allocation group. Each participant will be assigned a unique study 178 patient identification number once they have given informed consent and eligibility has been 179 confirmed. The central trial pharmacist will prepare a 12-week package of treatment bearing 180 the patient's name and ID number and send it to the site pharmacy. Thus, the site pharmacy 181 will not know the treatment allocated to the patient. A study information leaflet will be given to the participant, explaining that they are in a clinical trial and that in addition to TAU they 183 are taking a placebo or simvastatin. This leaflet will also have the name of the local PI's.

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Allocation will be masked from study investigators and co-investigators until participants 186 have completed all follow-ups and the database is cleaned and locked. The trial pharmacist at 187 the central pharmacy will keep the drug codes. There will be detailed protocols regarding   Simvastatin will be started at a dose of 20mg daily. Assessments will be at baseline, weeks 2, The clinical team and consultant psychiatrist will continue to oversee routine care for each 206 participant although research assistants will be contactable for the duration of the study to 207 respond to any concerns. Demographic data will be collected by RAs at baseline and will 208 include age, gender, marital status, socio-economic status, highest level of education, 209 smoking status, and concomitant medication.  . We will also assess changes in body mass index (BMI) from baseline to 231 week 12. All scales have been validated for use in the Urdu language and have been used in 232 previous studies in Pakistan [24]. Adverse effects will be monitored using a side effect 233 assessment scale based on the product monograph of simvastatin.

Statistical Analysis
Initial descriptive analysis will be conducted to study the profile of the subjects and  The main analysis will follow the Intention-to-treat (ITT) principle in which subjects are 258 assigned to treatment groups as randomized. Subjects that drop out of the study will be 259 included in the analysis provided that they have a baseline score for the outcome. For the 260 primary hypothesis, the MADRS scores at week 12 will be compared between groups using a 261 mixed effect model. The outcome for the model will be all post-baseline MADRS scores and 262 the fixed effects will include baseline MADRS scores, treatment group, time (post-baseline 263 timepoints) and a treatment group by timepoint interaction. To account for the dependencies 264 between repeated measures on the same patients, an intercept for each individual will be 265 included as a random effect. A linear contrast will be used to test the primary hypothesis, the 266 difference between groups in at week 12 in MADRS scores. Given the modest sample size it 267 will likely not be possible to use as random slope for each subject, however the covariance 268 matrix of the residuals of the model can be allowed to correlate to account for dependencies 269 across time. Two tailed tests and an alpha level of 0.05 will be used for significance. All Secondary analyses will use similar mixed models to that of the primary outcome, baseline 276 adjusted with time, treatment group and the interaction between treatment group and time as 277 independent variables. As for the primary outcome, the main timepoint of interest is 12 week 278 follow up and treatment effects will be determined by contrasts at the measured timepoint.

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To compare response and remission rates between groups logistic regression will be used in   It is likely there will be some drop-out of participants from the trial. Baseline predictors of 294 missingness can be identified using logistic regression with the outcome (missing or not).

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Mixed effect models fitted through maximum likelihood can use all available information in 296 the data potentially avoiding removal of dropout subjects from the analysis. Moreover, by 297 including baseline predictors of missingness in the statistical models, the analysis may assume the data to be missing at random (MAR). Diagnostic analysis will be conducted 299 through checking residuals for outliers, influential data points and normality. If outliers or 300 influential points are found a sensitivity analysis will conducted after removing such points to 301 see if the main findings change.

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The exploratory hypothesis that baseline lipid/CRP levels will affect response to simvastatin 304 will be tested by adding the baseline lipid/CRP to a model for the primary outcome at 12 305 weeks, adjusted for baseline and including a treatment group by baseline lipid/CRP. The 306 lipid/CRP level will be considered moderators if interaction with treatment group is 307 significant (at significance level of 0.05, using bootstrapping for inference and construction 308 of confidence intervals). If this is the case, exploratory plots that look at the group effect at 309 different levels of the moderators will be used to study the nature of the moderation. In order to test the hypothesis that changes in peripheral levels of lipids/CRP will be a 312 mediator in the path between treatment and change in MADRS scores, an initial descriptive 313 analysis will be conducted to look at the bivariate association between treatment group and 314 change in lipid/CRP levels, and between change in lipid/CRP (at 4 and 12 weeks) and change 315 in MADRS scores. A mediation model will then be fitted to the data that joint models the   For data security, consent forms and paper copies of assessment tools having any identifying 337 information such as name, address or phone number of participants will all be stored in 338 locked filing cabinets in a secure office. All computerised data will be encrypted and 339 password protected. We will also maintain quarterly site audits of the data and security 340 protocols across each site. These audits will be independent from the investigators and the  The responsibility of TSC will be to offer the overall supervision and monitoring of conduct 345 of the trial. The TSC will be independent of the investigators, their employing bodies, funders 346 and sponsors. The TSC will monitor overall trial progress, conduct and will also advise on 347 scientific credibility. The TSC will reflect and act, as suitable, upon the recommendations of